Klinikum Görlitz

BACKGROUND: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity. OBJECTIVE: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus. METHODS: Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%). RESULTS: Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of ≤ 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades ≤ 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions ≥ 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome. CONCLUSION: This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients.

The mechanism of recurrent sustained ventricular tachycardia (VT) was evaluated in 21 patients. Re-entry as the mechanism for VT was suggested by a) the reproducible initiation (19) and termination (15) of the arrhythmia by programmed stimulation. The rate, ventricle of origin, and stimulation site determined the method of termination. One VPD was usually required with VT rates less than 175/min and/or ventricle of origin ipsilateral to the stimulation site, while two VPDs were usually required for VT with faster rates originating in a contralateral ventricle. The proximal His-Purkinje system (HPS) was not required for initiation or maintenance of VT. Evidence localizing the site of re-entry to a small portion of the ventricles included: a) ventricular capture by ventricular premature depolarizations (VPDs) or pacing (VP) without terminating VT (5), b) sinus capture following VPDs and/or supraventricular fusions without terminating VT (12), and c) atrial pacing normalizing the QRS and H-V intervals without terminating VT (5).

Twenty patients with recurrent sustained ventricular tachycardia (VT) underwent serial electrophysiological studies (EPS) 1) to determine the predictive value of the EPS in the selection of antiarrhythmic therapy, and 2) to establish the therapeutic efficacy of available antiarrhythmic agents. In each patient VT could be reproducibly initiated by programmed stimulation. After control EPS, the effects of several drugs (lidocaine, procainamide, quinidine, disopyramide and diphenylhydantoin) on the ability to initiate VT were assessed. An oral regimen was chosen on the basis of acute EPS and its effectiveness was evaluated by repeat EPS in 24--72 hours. Blood levels achieved acutely were used as guidelines to chronic therapy. In 14 patients the initiation of VT was prevented by the acute administration of one or more agents. In 13 of these patients, a chronic oral regimen based on these results prevented recurrence of VT with a three- to 27-month follow-up. In the remaining patient, oral therapy could not achieve blood levels of procainamide shown to be effective intravenously, and VT recurred. In six patients no single drug or drug combination was effective during acute EPS, and VT recurred in all while on therapy with the agent shown to make initiation of VT most difficult. Procainamide prevented VT in nine patients; quinidine in three patients; lidocaine in three patients; diphenylhydantoin in two patients; and disopyramide in one patient. The mean duration of EPS studies was 4.5 days. This study suggests that serial EPS provides rapid identification of successful antiarrhythmic therapy and can predict in which patients conventional therapy would be ineffective, thereby identifying patients requiring more aggressive modes of therapy.

Variations in the frequency of ventricular premature depolarizations (VPDs) were evaluated with three consecutive 24-hour long-term electrocardiography monitor recordings from 15 clinically stable patients with various cardiac disorders. Mean hourly VPD frequencies ranged from 37--1,801 per hour. Data were subjected to 4 and 5 factor nested analyses of variance. The extent of spontaneous variation in arrhythmia frequency that occurred in individual patients from day to day was 23%, between 8-hour periods within days was 29%, and from hour to hour was 48%. In addition, the variability between repeated three-day monitoring periods over time was quantified in five patients and found to be 37%. This analysis determined that to distinguish a reduction in VPD frequency attributable to therapeutic intervention rather than biologic or spontaneous variation alone required a greater than 83% reduction in VPD frequency if only two-24-hour monitoring periods were compared, and greater than 65% reduction if two 72-hour periods were compared. The limitations of routine 24-hour electrocardiographic monitoring must be considered in diagnostic and therapeutic decision-making.

Twelve patients with medically refractory ventricular tachycardia secondary to ischemic heart disease underwent surgery for cure of their arrhythmia. Preoperatively, the tachycardia could be reproducibly initiated and terminated in each patient by programmed stimulation. In all instances, intraoperative mapping localized the tachycardia to the border of the aneurysm, a site not routinely resected during aneurysmectomy. In nine instances, the area of origin involved the septum. During bypass the tachycardia could still be induced after standard aneurysmectomy or ventriculotomy in 11 of 12 patients. On the basis of intraoperative mapping, resection of endocardium in the area of origin (25--40% the circumference of the aneurysmectomy) up to normal muscle was performed. In one patient without a discrete aneurysm, endocardial excision alone through a ventriculotomy was performed. There was one operative death due to cardiogenic shock (preoperative ejection fraction 5%) and one late death due to rupture of a mycotic aneurysm in the pulmonary artery. Before discharge, all patients underwent a repeat relectrophysiologic study off antiarrhythmic agents and in none could ventricular tachycardia be initiated. Hemodynamic and angiographic catheterization showed improved hemodynamics and ejection fractions in all. The 10 survivors remained free of sustained ventricular tachycardia for 9--20 months, with one late nonarrhythmic death.

OBJECTIVE: Neuromyelitis optica (NMO) attacks often are severe, are difficult to treat, and leave residual deficits. Here, we analyzed the frequency, sequence, and efficacy of therapies used for NMO attacks. METHODS: A retrospective review was made of patient records to assess demographic/diagnostic data, attack characteristics, therapies, and the short-term remission status (complete remission [CR], partial remission [PR], no remission [NR]). Inclusion criteria were NMO according to Wingerchuk's 2006 criteria or aquaporin-4 antibody-positive NMO spectrum disorder (NMOSD). Remission status was analyzed with generalized estimating equations (GEEs), a patient-based statistical approach. RESULTS: A total of 871 attacks in 185 patients (142 NMO/43 NMOSD, 82% female) were analyzed. The 1,153 treatment courses comprised high-dose intravenous steroids (HD-S; n = 810), plasma exchange (PE; n = 192), immunoadsorption (IA; n = 38), other (n = 80), and unknown (n = 33) therapies. The first treatment course led to CR in 19.1%, PR in 64.5%, and NR in 16.4% of attacks. Second, third, fourth, and fifth treatment courses were given in 28.2%, 7.1%, 1.4%, and 0.5% of attacks, respectively. This escalation of attack therapy significantly improved outcome (p < 0.001, Bowker test). Remission rates were higher for isolated optic neuritis versus isolated myelitis (p < 0.001), and for unilateral versus bilateral optic neuritis (p = 0.020). Isolated myelitis responded better to PE/IA than to HD-S as first treatment course (p = 0.037). Predictors of CR in multivariate GEE analysis were age (odds ratio [OR] = 0.97, p = 0.011), presence of myelitis (OR = 0.38, p = 0.002), CR from previous attack (OR = 6.85, p < 0.001), and first-line PE/IA versus HD-S (OR = 4.38, p = 0.006). INTERPRETATION: Particularly myelitis and bilateral optic neuritis have poor remission rates. Escalation of attack therapy improves outcome. PE/IA may increase recovery in isolated myelitis.

Although the mechanism of most episodes of recurrent ventricular tachycardia (VT) is believed to be re-entry, definitive proof of this hypothesis has heretofore been unavailable in man. Using programmed stimulation and ventricular endocardial mapping we studied three patients in whom the initiation of VT was dependent upon developing a critical degree of fractionation and delay in local left ventricular electrograms. When electrical activity spanned diastole, VT ensued. Maintenance of VT was associated with continuous electrical activity resembling "local fibrillation" while termination of VT required cessation of this continuous activity. During sinus rhythm the electrogram recorded from the areas which subsequently developed continuous activity showed markedly fractionated and prolonged electrical activity exceeding 100 msec in duration. We feel these observations of the temporal relationship of continuous activity with the development of VT represent the first documentation of the re-entrant nature of this arrhythmia in man.

Endocardial ventricular mapping of 21 ventricular tachyardias (VT) in 17 patients was performed using electrode catheters. Activation at multiple left and right ventricular sites was utilized to determine the site of origin of the VT. Eleven VT had a left bundle branch block pattern (VT-LBBB) and 10 VT had right bundle branch block pattern (VT-RBBB). In all VT-RBBB the earliest site of activation was in the LV or septum. In VT-LBBB the earliest site was RV (4/11), LV (5/11) and septum (2/11). All ventricular tachycardias with QRS less than 140 msec arose in the septum. In patients with an aneurysm, the site of origin of ventricular tachycardia was always in the aneursm. All VT-LBBB arising from the left ventricle originated in an aneurysm involving the septum. QRS changes during ventricular tachycardia were associated with alterations in the patterm of ventricular activation without alteration of the site of origin. In three patients the site of origin predicted by endocardial ventricular mapping was confirmed intraoperatively by epi- and/or endocardial mapping. We conclude that endocardial ventricular mapping demonstrates the limitations of the surface electrocardiogram in localizing the site of origin of ventricular tachycardia. The method may provide important data upon which the surgical therapy of ventricular tachycardia is based.

Dialysis and kidney transplant patients are vulnerable populations for COVID-19 related disease and mortality. We conducted a prospective study exploring the eight week time course of specific cellular (interferon-γ release assay and flow cytometry) or/and humoral immune responses (ELISA) to SARS-CoV-2 boost vaccination in more than 3100 participants including medical personnel, dialysis patients and kidney transplant recipients using mRNA vaccines BNT162b2 or mRNA-1273. SARS-CoV-2-vaccination induced seroconversion efficacy in dialysis patients was similar to medical personnel (> 95%), but markedly impaired in kidney transplant recipients (42%). T-cellular immunity largely mimicked humoral results. Major risk factors of seroconversion failure were immunosuppressive drug number and type (belatacept, MMF-MPA, calcineurin-inhibitors) as well as vaccine type (BNT162b2 mRNA). Seroconversion rates induced by mRNA-1273 compared to BNT162b2 vaccine were 97% to 88% (p < 0.001) in dialysis and 49% to 26% in transplant patients, respectively. Specific IgG directed against the new binding domain of the spike protein (RDB) were significantly higher in dialysis patients vaccinated by mRNA-1273 (95%) compared to BNT162b2 (85%, p < 0.001). Vaccination appeared safe and highly effective demonstrating an almost complete lack of symptomatic COVID-19 disease after boost vaccination as well as ceased disease incidences during third pandemic wave in dialysis patients. Dialysis patients exhibit a remarkably high seroconversion rate of 95% after boost vaccination, while humoral response is impaired in the majority of transplant recipients. Immunosuppressive drug number and type as well as vaccine type (BNT162b2) are major determinants of seroconversion failure in both dialysis and transplant patients suggesting immune monitoring and adaption of vaccination protocols.

Surgical resection of the endocardium and subendocardium often abolishes chronic recurrent sustained ventricular tachycardia in patients with healed myocardial infarcts or ventricular aneurysms, presumably by interrupting the reentrant pathway. To define the morphologic characteristics of cells in the reentrant pathway, we studied the histology and ultrastructure of the endocardial resections of 23 patients who underwent this procedure. Bundles of apparently viable myocardial fibers embedded in dense fibrous tissue were identified throughout the endocardial resections from all patients. These bundles of cells were separated from one another by fibrous tissue but extended uninterrupted to the margins of the surgical resection. In 14 patients Purkinje fibers were identified beneath the thickened endocardium whereas the remaining bundles were composed of ventricular muscle. The Purkinje fibers appeared to have normal ultrastructure and ventricular cells with both normal and abnormal ultrastructures were present. The abnormal muscle cells were characterized by loss of contractile elements, aggregates of dilated sarcoplasmic reticulum, and osmiophilic dense bodies. The sarcolemma was intact and the nuclear chromatin was evenly dispersed suggesting that these cells were still viable. The abnormal structure and arrangement of the surviving cardiac fibers in the endocardium may cause the abnormal electrophysiologic function that results in ventricular tachycardia.

This article examines and explains the committee system of the EU as a crucial property of the EU governance system using a database on the European Commission's experts groups. What is the extent of the expert consultative system? What is the distribution of expert groups? Are these groups best understood as loose networks or do they constitute a stable, well-established consultative system? We observe a proliferation of expert groups over time and across sectors. They have become permanent properties of the EU governance system; yet they are remarkably unevenly distributed among different policy domains. Sectoral differentiation is accentuated by weak horizontal coordination between the Directorates-General. We argue that this heterogeneity is not only a result of deliberate design attempts and differences in policy tasks, but also the result of differences in legal and administrative capabilities, as well as the gradual development of different routines and norms among the DGs.

OBJECTIVE: To analyze whether 1 of the 2 apheresis techniques, therapeutic plasma exchange (PE) or immunoadsorption (IA), is superior in treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for complete remission (CR). METHODS: This retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group, a nationwide network established in 2008. It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or with aquaporin-4 (AQP4-ab)-antibody-seropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March 2013. Besides descriptive data analysis of patient and attack characteristics, generalized estimation equation (GEE) analyses were applied to compare the effectiveness of the 2 apheresis techniques. A GEE model was generated to assess predictors of outcome. RESULTS: = 0.046). CONCLUSIONS: Our findings suggest early use of an apheresis therapy in NMOSD attacks, particularly in AQP4-ab-seropositive patients. No superiority was shown for one of the 2 apheresis techniques. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with NMOSD, neither PE nor IA is superior in the treatment of attacks.

Ventricular activation during ventricular tachycardia was studied by intraoperative epicardial and endocardial mapping in 21 patients with coronary artery disease and previous myocardial infarction who underwent operation for recurrent ventricular tachycardia. Twenty-nine morphologically distinct tachycardias were mapped; 18 tachycardias had a right bundle branch block morphology and 11 had a left bundle branch block morphology. After cannulation for bypass, the tachycardias were induced and electrograms were recorded at 55-75 epicardial sites. After starting cardiopulmonary bypass, the infarction was incised and electrograms were recorded at 28-55 left ventricular endocardial sites during ventricular tachycardia. All mapping data were analyzed with three simultaneously recorded ECG lead and two reference electrograms. Earliest activation in all tachycardias occured on the endocardial surface of the infarction. In each tachycardia, endocardial electrical activity was recorded before the onset of the QRS complex. Earliest epicardial activation in the 29 tachycardias occurred 10 msec after the onset of QRS complex. Epicardial breakthrough occurred on the right (19 tachycardias) as well as the left ventricle (10 tachycardias). We conclude that ventricular tachycardia associated with ischemic heart disease originates near the endocardial surface of the left ventricle along the border of the infarction and that epicardial mapping alone is insufficient to identify the site of origin of these tachycardias.

SUMMARY The QRS morphology of the 12-lead ECG of 41 morphologically distinct ventricular tachycar-dias (VT) was correlated with their site of origin as determined by catheter and intraoperative mapping. Twenty-two VT patterns had a right bundle branch block (VT-RBBB) morphology and 19 a left bundle branch block (VT-LBBB) morphology. All VT-RBBBs arose in the left ventricle. All 16 VT-LBBBs in patients with coronary artery disease (CAD) arose from the LV at sites on or adjacent to the septum. Three VT-LBBBs in patients without CAD arose in the right ventricle. The 12-lead ECG could not precisely identify the site of origin in patients with CAD but could differentiate anterior from posterobasal regions, particularly in VT-LBBB. The ECG was less useful in localizing VT-RBBB because of overlapping patterns. General patterns that were useful in differentiating anterior from posterobasal sites of origin included: (1) The presence of a q wave in leads 1 and V,, was seen in VT-RBBB or VT-LBBB originating anteriorly but not in VT of postero-basal or posterior septal origin. (2) R waves in leads 1 and V, to V, in VT-RBBB, and in leads 1, V2, V3 and V6 in VT-LBBB were specific for a posterior origin, and not observed in VT of anterior origin. (3) In VT-LBBB with a superior axis, a q wave in leads 1 and V6 was specific for origin along the inferior aspect of the anterior septum. (4) All VT-LBBB with an inferior and rightward axis originated from the superior aspect of the anterior septum. We conclude that although selected ECG features are useful in locating the origins of VT,

Two or more morphologically distinct ventricular tachycardias were observed during electrophysiologic study in 14 patients with chronic sustained ventricular tachycardia. Nine of these patients had clinical ventricular tachycardia with multiple morphologies. During the study 13 patients manifested both right bundle branch block (RBBB) and left bundle branch block (LBBB) morphologies. The remaining patient had RBBB with both right and left axis deviation. Changing morphologies were observed spontaneously in four patients and could be produced in all 14 by ventricular stimulation. In 12 patients both RBBB and LBBB originated in the left ventricle, and in 11 of these patients, from within a left ventricular aneurysm. Diastolic fragmented activity representing reentry was unchanged during both morphologies in four patients and during one morphology in five patients. Epicardial mapping confirmed the aneurysm as the site of origin of multiform ventricular tachycardias in two patients. Our data suggest that 1) ventricular tachycardia is frequently pleomorphic; 2) multiple morphologies usually represent variable exit sites and/or ventricular activation during the same tachycardia; and 3) there is a frequent association of pleomorphic ventricular tachycardia with left ventricle aneurysm.

We performed a genome‐wide association study in 1,194 controls and 150 patients with anti‐ N ‐methyl‐D‐aspartate receptor (anti‐NMDAR, n = 96) or anti‐leucine‐rich glioma‐inactivated1 (anti‐LGI1, n = 54) autoimmune encephalitis. Anti‐LGI1 encephalitis was highly associated with 27 single‐nucleotide polymorphisms (SNPs) in the HLA‐II region (leading SNP rs2858870 p = 1.22 × 10 −17 , OR = 13.66 [7.50–24.87]). Potential associations, below genome‐wide significance, were found with rs72961463 close to the doublecortin‐like kinase 2 gene ( DCLK2 ) and rs62110161 in a cluster of zinc‐finger genes. HLA allele imputation identified association of anti‐LGI1 encephalitis with HLA‐II haplotypes encompassing DRB1*07:01, DQA1*02:01 and DQB1*02:02 ( p &lt; 2.2 × 10 −16 ) and anti‐NMDAR encephalitis with HLA‐I allele B*07:02 ( p = 0.039). No shared genetic risk factors between encephalitides were identified. Ann Neurol 2018;83:863–869

OBJECTIVE: To analyse predictors for relapses and number of attacks under different immunotherapies in patients with neuromyelitis optica spectrum disorder (NMOSD). DESIGN: This is a retrospective cohort study conducted in neurology departments at 21 regional and university hospitals in Germany. Eligible participants were patients with aquaporin-4-antibody-positive or aquaporin-4-antibody-negative NMOSD. Main outcome measures were HRs from Cox proportional hazard regression models adjusted for centre effects, important prognostic factors and repeated treatment episodes. RESULTS: 265 treatment episodes with a mean duration of 442 days (total of 321 treatment years) in 144 patients (mean age at first attack: 40.9 years, 82.6% female, 86.1% aquaporin-4-antibody-positive) were analysed. 191 attacks occurred during any of the treatments (annual relapse rate=0.60). The most common treatments were rituximab (n=77, 111 patient-years), azathioprine (n=52, 68 patient-years), interferon-β (n=32, 61 patient-years), mitoxantrone (n=34, 32.1 patient-years) and glatiramer acetate (n=17, 10 patient-years). Azathioprine (HR=0.4, 95% CI 0.3 to 0.7, p=0.001) and rituximab (HR=0.6, 95% CI 0.4 to 1.0, p=0.034) reduced the attack risk compared with interferon-β, whereas mitoxantrone and glatiramer acetate did not. Patients who were aquaporin-4-antibody-positive had a higher risk of attacks (HR=2.5, 95% CI 1.3 to 5.1, p=0.009). Every decade of age was associated with a lower risk for attacks (HR=0.8, 95% CI 0.7 to 1.0, p=0.039). A previous attack under the same treatment tended to be predictive for further attacks (HR=1.5, 95% CI 1.0 to 2.4, p=0.065). CONCLUSIONS: Age, antibody status and possibly previous attacks predict further attacks in patients treated for NMOSD. Azathioprine and rituximab are superior to interferon-β.

BACKGROUND AND PURPOSE: EmboTrap is a novel stent retriever designed to achieve rapid and substantial flow restoration in acute ischemic stroke secondary to large-vessel occlusions. Here, we evaluated EmboTrap's safety and efficacy compared with established stent retrievers. METHODS: ARISE II (Analysis of Revascularization in Ischemic Stroke With EmboTrap) was a single-arm, prospective, multicenter study, comparing the EmboTrap device to a composite performance goal criterion derived using a Bayesian meta-analysis from the pivotal SWIFT (Solitaire device) and TREVO 2 (Trevo device) trials. Patients at 11 US and 8 European sites were eligible for inclusion if they had large-vessel occlusions and moderate-to-severe neurological deficits within 8 hours of symptom onset. The primary efficacy end point was achievement of modified Thrombolysis in Cerebral Ischemia (mTICI) reperfusion scores of ≥2b within 3 EmboTrap passes as adjudicated by the core laboratory. The primary safety end point was a composite of symptomatic intracerebral hemorrhage and serious adverse device effects. Secondary end points included functional independence (modified Rankin Scale, 0-2) and all-cause mortality at 90 days. RESULTS: value, <0.0001), and mTICI 2c/3 was 65%. After all interventions, mTICI 2c/3 was achieved in 76%, and mTICI ≥2b was 92.5%. The rate of first pass (mTICI ≥2b following a single pass) was 51.5%. The primary safety end point composite rate of symptomatic intracerebral hemorrhage or serious adverse device effects was 5.3%. Functional independence and all-cause mortality at 90 days were 67% and 9%, respectively. CONCLUSIONS: The EmboTrap stent-retriever mechanical thrombectomy device demonstrated high rates of substantial reperfusion and functional independence in patients with acute ischemic stroke secondary to large-vessel occlusions. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02488915.

A semi-quantitative evaluation method has been developed to map integrated fossil plant records (leaf, fruit, and pollen assemblages) in terms of zonal vegetation. It incorporates taxonomy, physiognomy, and autecological features of the fossil plants. To derive vegetation types, the final stage of this method involves a quantitative evaluation. The maps presented here are based on 198 organ assemblages from 173 localities and stratigraphic levels of the Miocene–early Pliocene across Europe. They cover three time intervals: (1) 4–7 Ma (Messinian–middle Zanclean; late Miocene–early Pliocene); (2) 8.5– 12 Ma (latest Serravallian–middle Tortonian); and (3) 14–17 Ma (late Burdigalian–late Langhian). We also look at the interval 13–14 Ma (late Langhian–early Serravallian). They not only show vegetation types but offer more detailed information on the composition of these associations (proportions of major components). The major zonal vegetation types recognized here are broad-leaved deciduous forests, mixed mesophytic forests, broad-leaved evergreen forests, subhumid sclerophyllous forests, open woodlands, and xeric grasslands. Between 14 Ma and 17 Ma, broad-leaved evergreen forests were widespread, and subhumid sclerophyllous forests were more strongly represented in western parts of Central Europe than in eastern parts. In the interval 8.5–12 Ma, broad-leaved deciduous forests largely replaced the evergreen forests, although these were still present in some refugia (e.g., the Lower Rhine embayment and northern Balkan peninsula), and first records of xeric grasslands are found along the northern margin of the Black Sea. The more discontinuous record available from 4 Ma to 7 Ma indicates that broad-leaved evergreen forests still occurred in northern parts of the Mediterranean (northern Italy, Balkan peninsula), while open woodlands increasingly appeared in central and southern parts of Italy and Greece.

Ventricular tissues were obtained at the time of operation from 12 patients who underwent aneurysmectomy or mitral valve replacement. The electrophysiologic characteristics of these tissues were determined in a tissue bath using microelectrodes. Normal-appearing action potentials were recorded from surviving Purkinje fibers and ventricular muscle cells within infarcted ventricular tissues. Normal muscle action potential recordings from infarcted tissues were similar to action potentials from noninfarcted papillary muscles, except that the duration of the action potential was significantly longer in the former. In other areas slow response potentials were recorded. These action potentials conducted slowly and were eliminated by verapamil. We observed verapamil-sensitive slow response automaticity, but this did not correlate with ventricular tachycardias, present in three patients. Variable amplitude responses arising from normal resting potentials and characterized by stimulus intensity-dependent changes in action potential amplitude were recorded in tissues from two patients. These potentials had many characteristics similar to the slow response, but were not eliminated by verapamil. We also saw inexcitable cells with both normal and abnormal resting potentials. The heterogeneous electrophysiologic characteristics of these tissues provide a likely substrate for arrhythmias and may be the source of the ectopic ventricular rhythms observed in these patients.